Method of treating hyperchlorhydria and/or associated conditions

ABSTRACT

A method for preventing the secretion of excessive amounts of hydrochloric acid in the stomach of humans suffering from hyperchlorhydria and/or associated conditions, by administering an effective amount of a compound of the formula   WHEREIN R is hydrogen or methyl.

United States Patent Lippmann 1 June 13, 1972 METHOD OF TREATINGHYPERCHLORI'IYDRIA AND/OR ASSOCIATED CONDITIONS Wilbur Lippmann,Montreal, Quebec, Canada Inventor:

Assignee: Ayerst, McKenna and Harrison, Limited,

St. Laurent, Quebec, Canada Filed: Oct. 14, I969 Appl. No.: 866,396

Related US. Application Data Continuation-impart of Ser. No. 826,657,May 21, 1969.

US. Cl ..424/275, 424/285, 424/330 Int. Cl. ..A6lk 27/00 Field of Search..424/275 References Cited FOREIGN PATENTS OR APPLICATIONS 9/1966Belgium Primary Examiner-Stanley J. Friedman Attorney-Vito VictorBellino. Andrew Kafka. Joseph Mnrlin Weigman, Dm'ght J. Potter andRobert Wiser [5 7] ABSTRACT U11 Ull wherein R is hydrogen or methyl.

5 Claims, N0 Drawings METHOD OF TREATING HYPERCHLORHYDRIA AND/ORASSOCIATED CONDITIONS This Application is a continuation-in-part of myearlier application Ser. No. 826,657, filed May 21, 1969.

This invention relates to a method for preventing the secretion ofexcessive amounts of hydrochloric acid in the stomach of humanssufiering from hyperchlorhydria and/or associated conditions. Since theusual peptic ulcer is frequently accompanied by, or the result of,hyperchlorhydria, my method is especially useful in the treatment ofpeptic ulcers and associated abnormal conditions of the gastrointestinaltract.

1 have found that the chemical compounds of the following formulaseither in their base forms, or in the form of their acid addition saltswith pharmaceutically acceptable acids, are particularly effective inpreventing the excessive secretion of hydrochloric acid.

The compounds may be represented by the following foron:3 CH3 CH3 0113CH; H;

in which R represents the phenyl or the cyano group, and R R and Rrepresent hydrogen or methyl; R represents hydrogen or methyl; and Rrepresents hydrogen or methyl. The chemical names of the compoundsrepresented by the above formulas are as shown below.

Compounds of formula I are:

N ,3 ,3-trimethyll -phenyll -phthalanpropylamine N,N,3 ,3-tetramethyll-phenyl- 1 -phthalanpropylamine l-cyano-N,3 ,3-trimethyll-phthalanpropylamine l-cyano-N,N,3 ,3-tetramethyl-phthalanpropylamineN,N,B,3 ,3-pentamethyll phenyll -phthalanpropylamine 3 ,3-dimethyll-phenyll -phthalanpropylamine Compounds of formula ll are:

N,3 ,3-trimethyll -phenyll -benzo[ c lthiop henepropylamine N,3,3-tetramethyll -phenyll -benzo[ c]thiop henepropylamine Compounds offormula III are:

N,3 ,3 -trimethyll -phenyll -indanpropylamine N,N,3,B-tetramethyll-phenyll -indanpropylamine.

The compounds of formula I have been described in a paper by P. V.Petersen et al., in Acta Pharmacol. et Toxicol. vol. 24, p. 121 (1966),in Belgian Pat. No. 678,035, published Sept. 19. 1966, and in SouthAfrican Pat. No. 67/1261, published July 31, 1967. Methods for theirpreparation are also disclosed in the above patents.

The compounds of formula ll have been described by Carlsson et al. inBrit. J. PharmacoL, vol. 36, p. 18 (1969), and their methods ofpreparation are disclosed in Belgian Pat. No. 709,229, published July 1l, 1968.

The compounds of formula lll have been described in the paper byPetersen et al. cited above, and methods for their preparation aredisclosed in Belgian Pat. No. 687,628, published Mar. 1, 1967 and inNetherlands Pat. No. 67,04297, published Sept. 29, 1967.

The acid addition salts of the above compounds are prepared by reactingthe base with either one equivalent or preferably an excess of theappropriate acid in an organic solvent, such as ether or anethanol-ether mixture. These salts, when administered to humans, possessthe same activity as the base itself, in preventing the secretion ofexcessive amounts of hydrochloric acid. For many purposes it ispreferable to administer the salts rather than the base compound. Amongthe acid accition salts suitable for this purpose are salts such as thesulfate, phosphate, lactate, tartrate, maleate, citrate andhydrochloride. The hydrochloride salts are especially convenient. Boththe base compounds themselves and the above acid addition salts have thedistinct advantage of possessing a relatively low order of toxicity.

The compounds of formulas I, 1], and Ill and their acid addition saltswith pharmaceutically acceptable acids may be administered to humanssuffering from hyperchlorhydria or associated conditions, for thepurpose of preventing secretion of excessive amounts of the hydrochloricacid in the stomach and gastrointestinal tract thereof, either orally orparenterally. For many reasons oral administration is preferred.

The compounds are soluble in a wide variety of pharmaceuticallyacceptable solvents and may readily be made up in solvents for oraladministration. They may also be prepared with suitable carriers to formtablets or capsules. Alternatively, they may be suspended in suitablesuspending agents and administered in this form. When any of thecompounds listed above of formulas I, ll, and III in which R, R, R, R, Rand R are as defined above or their acid addition salts withpharmaceutically acceptable acids are prepared for oral administration,they may, for example, be incorporated with the usual excipients orcarriers, such as lactose, starch or sucrose, in the form of capsules ortablets containing from 10-50 mg of the active ingredient per capsule ortablet. These pharmaceutical preparations may contain the usual coloringagents, preservatives or other usual ingredients. When liquidpreparations are preferred for oral ingestion, the compounds or theiracid addition salts, described above, may be dissolved or suspended in asuitable nontoxic carrier, such as, distilled water aqueous alcohol, ora pharmaceutically acceptable oil. The concentration of the active agentis selected to provide a generally useful composition.

A typical composition for oral ingestion, for example, may be asolution, containing 20 to 50 mg of the compound of formula lN,3,3-trimethyll -phenyll -phthalanpropylamine hydrochloride or thecompound of formula IIN,3,3-trimethyll-phenyl-l-benzo[c]thiophenepropylamine hydrochloride permilliliter to distilled water, rendered isotonic by the addition theretoof sodium chloride, sodium citrate or glucose. Similar compositions mayalso be prepared with the other compounds listed above of formulas l,II, and III in which R, R R", R", R and R are as defined above.

Such solutions or suspensions may also contain the usual preservatives,sweetening agents, and other agents which are present in conventionalliquid pharmaceutical preparations.

For parenteral administration,N,3,3-trimethyl-l-phenyl-lphthalanpropylamine or N,3,3-trimethyllphenyll Benzo[c]t hiophene propylamine or their acid addition salts withpharmaceutically acceptable acids may be dissolved or suspended insuitable sterile liquid carriers such as distilled water or oils ofsynthetic, animal, petroleum or vegetable origin, for example, soybeanoil, sesame oil, mineral oil or propylene glycol. The usualpreservatives and other ingredients used for pharmaceutical preparationsfor parenteral dose may also be incorporated. The concentration of theactive agent in these preparations for parenteral use is selected toprovide a generally useful composition. A typical composition wouldordinarily constitute from about 2 to 5 percent by weight, of N,3,3-trimethyll -phenyl-l -phthalanpropylamine hydrochloride or of N,3,B-trimethyll -phenyll benzo[c]thiophenepropylamine hydrochloride insesame oil with 1.5 percent benzyl alcohol as a preservative. Similarcompositions may also be prepared with any of the other compounds listedabove of formulas I, II, or III, in which R, R R, R", R and R are asdefined above.

When utilizing any of the compounds listed above of formulas I, ll, orIII in which R, R R", R, R and R are as defined above or their acidaddition salts, described above, as agents for combatting or preventinghyperchlorhydria, and/or associated conditions, the total dose of activeagent may range from approximately 0.1 mg per kilogram of body weight tomg per kilogram of body weight, with a preferred dosage range of from0.2 to 2.0 mg per kilogram body weight. Generally, a parenteral dose isadministered once a day, whereas the daily oral dose is administered inthree or four applications. Such doses are considered to be effectiveamounts when, following their administration, either the amounts ofhydrochloric acid secreted within a specified period of time by thehuman so treated are significantly reduced, or when the subjectivesymptoms complained of by said human being are reported as havingdisappeared, or being ameliorated or reduced in severity following suchtreatment.

The effects of any of the compounds listed above of formulas I, II andIII in which R, R R R, R and R are as defined above and their acidaddition salts with pharmaceutically acceptable acids as agents forpreventing hyperchlorhydria and inhibiting hydrochloric acid secretionmay be demonstrated by the use of rats, more especially the Shay rat.The rat is the preferred experimental mammal for demonstrating theactivity of agents effecting gastric acid secretion and it has beenwidely used in experimental medicine for this purpose. For instance, onp. 149 in Pathophysiology of Peptic Ulcer, published by McGillUniversity Press, Montreal, Canada in 1963, Skoryna states that many ofthe drugs now in use in human medicine for the treatment of peptic ulcerhave been evaluated by the Shay rat method. It is recognized by skilledpharmacologists that results obtained in the Shay rat in the evaluationof gastric acid conditions are translatable to results that will beobtained when the same drug is administered to human beings. For thevalue of the Shay rat in experimental gastroenterology, see also thearticle by Shay et al. in Gastroenterology, vol. 26 p. 906, 1954). Thisanimal is generally recognized as the preferred, or standard, animal foruse experimentally in testing drugs used to inhibit gastric acidsecretion.

More specifically, it has been demonstrated that when the compound offormula I N,3,B-trimethyl-l-phenyl-1-phthalanpropylamine or the compoundof formula II N,3,3-trimethyll-phenyl-l-benzo[c]thiophenepropylamine ortheir respective acid addition salts, preferably the above hydrochloridesalts, are administered to Shay rats in dosages of 0.625 mg. perkilogram of body weight, reduction in the basal hydrochloric acidsecretion to a value within the range of 57 percent to 64 percent ofcontrol values results. When the compounds were administered to Shayrats in dosages of 1.25 mg per kilogram of body weight an observedreduction of basal hydrochloric acid secretion from 44 percent to 49percent of control values occurred. Again, more specifically, theability of N,3,3- trimethyl-l-phenyl-l-phthalanpropylamine hydrochlorideor of N ,3,3 -trimethyll-phenyll Benzo[c thiophenepropylaminehydrochloride to inhibit the secretion of hydrochloric acid and preventulcer formation in rats, was demonstrated experimentally in accordancewith the method described by Brodie et al. in Proc. Soc. Exp. Biol. Med,vol. 1 13, p. 998 1963), this method having been modified to some extentin accordance with the procedure of Senay et al. as described in vol.124, p. 1,221 1967) of the same publication. In this modified procedurerats were injected intraperitoneally with pharmaceutical preparationscontaining the compound as active agent. The intraperitoneallyadministration of N,3,3- trimethyl-lphenyl-l-phthalanpropylaminehydrochloride in dosages of 6.3 i 1.4 milligrams per kilogram of bodyweight was found to protect 50 percent of the test animals from ulcerformation. Under the conditions of this test, 80-100 percent of theuntreated rats used as controls developed gastric lesions, consisting ofone or several macroscopical erosions of the glandular mucosa, oftenaccompanied by hemorrhage. Similar results were also obtained whensimilar doses of any of the other compounds listed above of formulas I,II, or III in which R, R, R, R, R and R are as defined above were used.

In a comparison with the known compound atropine sulfate, which ispresently utilized for preventing ulcer formation, while atropinesulfate was found to protect from 50 to 75 percent of the test animalswhen administered at dosages of 2 milligrams per kg of body weight, thetypical undesirable anticholinergic effects of atropine were clearlyobservable in the rats to whom the atropine sulfate had beenadministered. As contrasted with these undesirable effects theadministration of the compounds listed above of formulas I, II, or IIIin which R, R R, R, R and R are as defined above to the test animals inthe dosages referred to above were found not to result in any observableundesirable side effects, side effects resulting from anti-cholinergicactivity being conspicuously absent.

The following examples will illustrate this invention.

EXAMPLE 1 a. N,3,3,-trimethyl-1-phenyll-phthalanpropylaminehydrochloride or N,3,3-trimethyl-l-phenyl-l-benzo[c]thiophenepropylamine hydrochloride (20 g) is dissolved in 980 ml of distilledwater, the chloride (20 g) is dissolved in 980 ml of distilled water,the solution is made isotonic by addition of sodium chloride or sodiumcitrate or glucose, a preservative such as 0.1 percent weight by volumeof Methylparaban and 0.015 percent weight by volume of Propylparaban or0.5 percent weight by volume of chlorbutanol is added, the solution ismade up to 1,000 ml with distilled water, sterilized by autoclaving orsterile filtration, and filled into 2 ml ampoules or vials, to make asolution for parenteral administration containing 20 mg/ml of the activeingredient.

b. In the same manner, but using 50 g ofN,3,3-trimethyl-lphenyl-l-benzo[c]thiophenepropylamine hydrochloride, asolution for l-phenyll -thiophthalanpropylamine hydrochloride, asolution for parenteral administration containing 50 mg/ml of the activeingredient is obtained and is filled into 20 ml ampoules or vials.

c. N,3,3-trimethyll -phenyl- 1 -phthalanpropylamine hydrochloride orN,3,3-trimethyl-b l-phenyl-l-benzo[c ]thiophenepropylamine hydrochloride(20 g) is suspended in 965 g of sesame oil and 15 g of benzyl alcohol bymeans of a mechanical blender. The suspension is filled into 2 mlampoules or vials. After autoclaving, a suspension containing 2 percentof the active ingredient by weight is obtained for parenteraladministration.

d. Again in the same manner, but using 0.225 g, 0. 45 g, 2.5 g, 5.0 g,or 10.0 g of N ,3,3-trimethyl-l-phenyll-phthalanpropylaminehydrochloride or ofN,3,3-trimethyll-phenyl-lbenzolc]thiophenepropylamine hydrochloridealone, without additives or preservatives, solutions for parenteral ororal administration for pharmacological purposes containing 0.225 mg/ml,0.45 mg/ml, 2.5 mg/ml, 5.0 mg/ml, and 10.0 mg/ml of the activeingredient are obtained, respectively.

Similar solutions or suspensions are also prepared with any of the othercompounds listed above of formulas I, II, or III in which R, R R, R, Rand R are as defined above.

EXAMPLE 2 a. N,3,3-trimethyl- 1 -phenyl-l-phthalanpropylaminehydrochloride or N,3,3-trimethyl-1-phenyll -benzo[ c lthiophenepropylamine hydrochloride (50 g) is mixed with g lactone, 44 gstarch, 4 g magnesium stearate and 2 g, sucrose. The mixture isgranulated with addition of a small amount of water, dried andcompressed into tablets weighing 250 mg each, to make l,000 tabletscontaining 50 mg each of the active ingredient.

b. In the same manner, but using 10 g of N,3,3-trimethyl-I-phenyl-l-pht.halanpropylamine hydrochloride or N,3,3- trimethyll-phenyl- 1 -benzo[ c ]thiophenepropylamine hydrochloride, g lactose, 44g starch, 4 g magnesium stearate, and 2 g sucrose, there are obtained1,000 tablets of 250 mg weight each, such tablets containing 10 mg eachof the active ingredient.

c. Again in the same manner, but using 25 g of N,3,3-trimethyl-l-phenyl-l-phthalanpropylamine hydrochloride or N,3,3-trimethyll -phenyll -benzo[c ]thiophenepropylamine hydrochloride, 175g lactose, 44 g starch, 4 g magnesium stearate, and 2 g sucrose, thereare obtained 1,000 tablets of 250 mg weight each, such tabletscontaining 25 mg each of the active ingredient.

Similar tablets are also prepared containing any of the other compoundslisted above of formulas I, II, or III in which R, R R", R, R and R areas defined above.

EXAMPLE 3 The inhibition of basal gastric acid secretory activity by N,3,3-trimethyll -phenyl- 1 -phthalaripropylamine hydrochloride or by N,3,3-trimethyll -phenyll benzo[c]thiophenepropylamine hydrochloride wasdetermined by a modified method of Shay et a]. cited above. CharlesRiver female albino rats (Candian Breeding Laboratories; 170-190 g) werecaged individually 48 hours prior to treating. After the first 24 hoursof food deprivation the animals were given access to 8 percent sucrosein 0.2 percent sodium chloride for 8 hours. Water was permitted adlibitum except during the 8 hours of sucrose. Three hours after thepyloric ligation the animals were anesthetized with ether and the amountof acid in the stomach determined by titration against 0.1N sodiumhydroxide in a direct reading pH meter to 7.0. There were four to nineanimals in each group.

When rats were subjected to the above procedure without treatment withN,3 ,3-trimethyll-phenyl- 1 -phthalanpropylamine hydrochloride or withN,3,3-trimethyl-l-phenyll-benzo[c]thiophenepropylamine hydrochlorideapproximately 0.45 milliequivalents of hydrochloric acid were secretedper rat during a period of 3 hours (0.44 10.03 to 0.47 10.04milliequivalents).

A solution of N,3,3-trimethyl-l-phenyl-l-phthalanpropylaminehydrochloride containing 0.225 mg/ml in sterile distilled water wasprepared, according to the procedure described in example 1 (d), and therats to be treated with N,3 ,3-trimethyll -phenyll -phthalanpropylaminehydrochloride were administered with 0.5 ml each of the above solution,equivalent to a dosage level of 0.625 mg/kg body weight. Thisadministration was carried out immediately following pyloric ligation,and the acid contents of the stomach were determined 3 hours later inthe same manner as described above. It was found that 0.27 10.03 to 0.2810.05 milliequivalents of hydrochloric acid had been secreted in theabove 3 hour period by the animals treated as above, corresponding to areduction to 57-64 percent of control values.

In another experiment a solution containing 0.45 mg/ml of N,3,3-trimethyll -phenyl- 1 -phthalanpropylamine hydrochloride, wasprepared as described in example 1 (d), and the rats were injectedintraperitoneally with 0.5 ml of that solution each in the same manneras described above, equivalent to a dosage level of 1.25 mg/kg bodyweight, It was found that 0.21 10.03 milliequivalents of hydrochloricacid had been secreted by the animals treated in the above manner duringthe standard 3 hour period, corresponding to a reduction of secretion ofhydrochloric acid to 49 percent of control values.

Using the same experimental procedure described above, it may be shownthat the administration of the remaining preparations described inexample 1 reduce the secretion of hydrochloric acid in the animalsrelative to control values.

Similar results were also obtained when similar dosages of N,3,3-trimethyll -phenyll -benzo[c ]thiophenepropylamine hydrochloride orany of the other compounds listed above of formulas I, II, or III inwhich R, R R R, R and R are as defined above were used.

EXAMPLE 4 Male albino rats of 170-190 g body weight each were restrainedin a plastic box equipped with baffles so as to make movements of theanimal impossible, and were kept at room temperature in this conditionfor 45 minutes. They were then exposed for 105 minutes to a temperatureof 5C. 1 hour later the rats were killed with ether and their stomachsremoved. The stomachs were cut open along the longest curvature and werethen unfolded for inspection. The results were evaluated visually in anall or none fashion based on the presence or the absence of lesionsindependent of their number and severity. Under those conditions -100percent of the untreated rats used as controls developed gastriclesions, consisting of one or several macroscopical erosions of theglandular mucosa, often accompanied by hemorrhage.

When rats were injected intraperitoneally 45 minutes before thebeginning of the above test with doses of the solutions ofN,3,3-trimethyll -phenyll -phthalanpropylamine hydrochloride describedin example 1(c) corresponding to 2.5 mg per kilogram body weight, 88percent of the rats thus treated showed gastric lesions as describedabove. When the same experiment was repeated with doses corresponding to5.0 mg per kilogram body weight, 50 percent of the rats thus treatedshowed the same type of gastric lesions. And when this same experimentwas repeated with doses corresponding to 10.0 mg per kilogram bodyweight, 36 percent of the rats thus treated showed the same type ofgastric lesions.

When the above results were statistically calculated by probit analysis,it was found that the effective dose of N,3,3- trimethyll-phenyll-phthalanpropylamine hydrochloride protecting 50 percent of therats (ED was 6.3 l.4 mg per kilogram body weight, and that such dosescaused no untoward efiects whatsoever. Similar results were alsoobtained when similar doses of any of the other compounds listed aboveof formulas I, II, or III, in which R, R R, R", R and R are as definedabove were used. Atropine in doses of 2 mg per kg body weight was usedin the above experiments as a standard control, and while the aboveamount of atropine protected about 50 percent of the animals, the toxicside effects of atropine were apparent.

In the appended claims, whenever the compound to be administered isnamed as the free base it is understood that such compound may also beadministered in the form of a pharmaceutically acceptable acid additionsalt thereof which is the full pharmaceutical equivalent of the compounditself.

I claim:

1. The method of preventing the secretion of excessive amounts ofhydrochloric acid in the stomach of humans which comprises administeringto a human suffering from hyperchlorhydria and/or associated conditionsan effective amount of a compound of the formula CH3 CH3 wherein R ishydrogen or methyl.

2. The method of preventing the secretion of excessive amounts ofhydrochloric acid in the stomach of humans as claimed in claim 1 inwhich the effective amount of the compound to be administered is withinthe range of from 0.1 to 10 mg per kilogram body weight.

3. The method as claimed in claim 1 in which the compound isN,3,3-trimethyl- 1 -phenyll -benzo[c]thiop henepropylamine.

4. The method as claimed in claim 1 in which the compoundN,3,3-trimethylld-phenyl-1-benzo[c]thiophenepropylamine is administeredin the form of its hydrochloride salt.

5. The method as claimed in claim 3 in which N,3,3- trimethyll -phenyl-1 -benzo[c lthiophenepropylamine is administered in amounts within therange of from 0.1 to 10 milligram per kilogram body weight.

2. The method of preventing the secretion of excessive amounts ofhydrochloric acid in the stomach of humans as claimed in claim 1 inwhich the effective amount of the compound to be administered is withinthe range of from 0.1 to 10 mg per kilogram body weight.
 3. The methodas claimed in claim 1 in which the compound is N,3,3-trimethyl-1-phenyl-1-benzo(c)thiophenepropylamine.
 4. The method asclaimed in claim 1 in which the compoundN,3,3-trimethyl-1-phenyl-1-benzo(c)thiophenepropylamine is administeredin the form of its hydrochloride salt.
 5. The method as claimed in claim3 in which N,3,3-trimethyl-1-phenyl-1-benzo(c)thiophenepropylamine isadministered in amounts within the range of from 0.1 to 10 milligram perkilogram body weight.